TEL-PDGFRβ is a fusion kinase that is associated with chronic myelomonocytic leukemia (CMML), a myeloproliferative disorder characterized by abnormal myelopoiesis, eosinophilia, myelofibrosis, and frequent progression to acute myeloid leukemia.
FIP1L1-PDGFRα is a fusion kinase associated with hypereosinophilic syndrome (HES) or chronic eosinophilic leukemia (CEL), a clonal myeloproliferative disorder associated with prominent blood eosinophilia and organ damage.
It has now been shown that pyrimidylaminobenzamide derivatives are active against the clinically relevant fusion kinases TEL-PDGFRβ and FIP1L1-PDGFRα, which are associated with the myeloproliferative diseases CMML and HES, respectively. Furthermore, such pyrimidylaminobenzamide derivatives are effective against myeloproliferative diseases caused by TEL-PDGFRβ and/or FIP1L1-PDGFRα. Pyrimidylaminobenzamide derivatives effectively inhibit growth of Ba/F3 cells transformed by both fusion kinases, and can inhibit phosphorylation of tyrosine residues in these fusion kinases as well as activation of their downstream signaling targets. Pyrimidylaminobenzamide derivatives are also effective in vitro against an imatinib-resistant T681I mutation in TEL-PDGFRβ. This residue corresponds to T315I in BCR-ABL, a mutation that confers imatinib resistance in patients, which is notoriously difficult to inhibit. Imatinib (International Non-proprietary Name) is a tyrosine kinase inhibitor which is marketed under the designation GLEEVEC® in the US and GLIVEC® in Europe.
It has now been found that pyrimidylaminobenzamide derivatives are useful in the treatment of TEL-PDGFRβ- or FIP1L1-PDGFRα-induced myeloproliferative diseases, especially for the curative and/or prophylactic treatment of myelomonocytic leukaemia, hypereosinophilic syndrome, chronic eosinophilic leukemia and hypereosinophilic syndrome with resistance to imatinib.